Alarming statistics on the spread of obesity include an increase in premature death from cardiovascular disease. Yet, the effects of over-nutrition on the heart are not well understood. We therefore propose to examine the "molecular footprints" of obesity in the heart, and identify mechanisms leading to impaired cardiac function in animal models, as well as in clinically obese patients undergoing gastric bypass surgery. Special emphasis is placed on the myocardial consequences of deranged glucose and fatty acid metabolism leading to a cardiomyopathy of obesity that is potentially reversible. The broad objective of this proposal is to test the hypothesis that abnormal accumulation of ,qlucose and fatty acid metabolites resulting from a loss of synchronization of substrate uptake and oxidation, induces glucolipotoxicity, and leads to contractile dysfunction of the heart. The first specific aim will define the process by which excess fuel supply (beyond the storage capacity of adipocytes) results in accumulation of lipotoxic compounds in the heart and in other organs (e.g. skeletal muscle). In genetic and diet-induced rat models of obesity we shall define the time course of adaptation and maladaptation to excess substrate availability. We shall also define the time course of reversal of obesity-induced changes by food restriction or surgical intervention (gastric bypass). The second specific aim will address potential mechanisms of glucolipotoxicity in heart, as well as in skeletal muscle. We shall examine gene expression, PKC activity, protein glycosylation, protein ubiquitinization, and programmed cell death. Selective activation of these different pathways may play a significant role in glucolipotoxicity. The third specific aim will apply insights gained from animal experiments to ascertain whether correlates of glucolipotoxicity exist in humans and test the hypothesis that weight loss reverses the maladaptive response in patients undergoing gastric bypass. We will define metabolic indices (BMI, insulin resistance, blood pressure, lipid profile, adipokine levels) and indices of cardiac function (by echocardiography) in tandem with skeletal muscle biopsies before, as well as three and nine months after surgery. Our Iong-term qoals are to define metabolic adaptation and maladaptation of the heart in clinically-relevant obesity, to transform the concept of glucolipotoxicity from an operational definition to a concrete physiological principle, and to establish a rationale for more effective treatment of obese patients with heart failure.